Membrane Disordering Effects of β-Amyloid Peptides

  • Gunter P. Eckert
  • W. G. Wood
  • W. E. Müller
Part of the Subcellular Biochemistry book series (SCBI, volume 38)


The interaction of Aβ with synaptosomal plasma membranes decreases membrane fluidity. Using model membrane/Iiposome systems the interaction of Aβ with specific lipids (e.g. phospholipids, gangliosides, cholesterol) has been defined. The formation of the β-sheet structure of Aβ when undergoing peptide aggregation is important for Aβ’s membrane perturbing properties. This effect can be correlated with the peptide length of Aβ, the longer Aβ1-42 having the greatest effect on membrane fluidity and on neurotoxicity.

Key words

β-amyloid (Aβ) membrane fluidity brain membranes cholesterol phospholipid ganglioside 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Arispe, N., and Doh, M., 2002, Plasma membrane cholesterol controls the cytotoxicity of Alzheimer’s disease AbetaP (1-40) and (1-42) peptides. FASEB J., 16: 1526–1536.PubMedCrossRefGoogle Scholar
  2. Arispe, N., Rojas, E., and Pollard, H.B., 1993, Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum. Proc. Natl. Acad. Sci. USA., 90: 567–571.PubMedCrossRefGoogle Scholar
  3. Avdulov, N.A., Chochina, S.V., Igbavboa, U., O’Hare, E.O., Schroeder, F., Cleary, J.P., and Wood, W.G., 1997a, Amyloid beta-peptides increase annular and bulk fluidity and induce lipid peroxidation in brain synaptic plasma membranes. J. Neurochem., 68: 2086–2091.PubMedCrossRefGoogle Scholar
  4. Avdulov, N.A., Chochina, S.V., Igbavboa, U., Vassiliev, A.V., Maletta, G.J., and Wood, W.G., 1996, Selective binding of cholesterol and fatty acids to amyloid beta peptide 1-40 aggregates: A fluorescent study. Soc. Neurosc. Abst., 22: 2112.Google Scholar
  5. Avdulov, N.A., Chochina, S.V., Igbavboa, U., Warden, C.S., Vassiliev, A.V., and Wood, W.G., 1997b, Lipid binding to amyloid beta-peptide aggregates: Preferential binding of cholesterol as compared with phosphatidylcholine and fatty acids. J. Neurochem., 69: 1746–1752.PubMedCrossRefGoogle Scholar
  6. Bodovitz, S., and Klein, W.L., 1996, Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein. J. Biol. Chem. 271: 4436–4440.PubMedCrossRefGoogle Scholar
  7. Brown, D.A., and London, E., 1998, Structure and origin of ordered lipid domains in biological membranes. J. Membr. Biol., 164: 103–114.PubMedCrossRefGoogle Scholar
  8. Burger, K., Gimpl, G., and Fahrenholz. F., 2000, Regulation of receptor function by cholesterol. Cell Mol. Life Sci, 57: 1577–1592.PubMedCrossRefGoogle Scholar
  9. Butterfield, D.A., Yatin, S.M., Varadarajan, S., and Koppal, T., 1999, Amyloid beta-peptide-associated free radical oxidative stress, neurotoxicity, and Alzheimer’s disease. Meth..Enzymol. 309: 746–768.PubMedCrossRefGoogle Scholar
  10. Chauhan, A., Chauhan, V.P.S., Brockerhoff, H., and Wisniewski, H.M., 1993, Effect of amyloid beta-protein on membrane properties. In: Alzheimer’s Disease: Advances in Clinical and Basic Research. Corain, B, Iqbal, K, Nicolini, M, Winblad, B, Wisniewski, H, and Zatta, P., (Eds.), John Wiley & Sons Ltd, New York, pp. 431–439.Google Scholar
  11. Chochina, S.V., Avdulov, N.A., Igbavboa, U., Cleary, J.P., O’Hare, E.O., and Wood, W.G., 2001, Amyloid beta-peptide(l–40) increases neuronal membrane fluidity. Role of cholesterol and brain region. J. Lipid Res. 42: 1292–1297.PubMedGoogle Scholar
  12. Cowbum, R.F., O’Neill, C., Bonkale, W.L., Ohm, T.G., and Fastborn, J., 2001, Receptor-G-protein signalling in Alzheimer’s disease, Biochem. Soc. Symp., XXX: 163–175.Google Scholar
  13. Drouet, B., Pincon-Raymond, M, Chambaz, J., and Pillot, T., 1999, Laminin 1 attenuates beta-amyloid peptide Abeta(l–40) neurotoxicity of cultured fetal rat cortical neurons. J. Neurochem. 73: 742–749.PubMedCrossRefGoogle Scholar
  14. Eckert, G.P., Cairns, N.J., Maras, A., Gattaz, W.F., and Müller, W.E., 2000, Cholesterol modulates the membrane-disordering effects of beta-amyloid peptides in the hippocampus: specific changes in Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 11: 181–186.PubMedCrossRefGoogle Scholar
  15. Eckert, G.P., Igbavboa, U., Muller, W.E., and Wood, W.G., 2003a, Lipid rafts of purified mouse brain synaptosomes prepared with or without detergent reveal different lipid and protein domains. Brain Res. 962: 144–150.PubMedCrossRefGoogle Scholar
  16. Eckert, G.P., Kirsch, C., Leutz, S., Wood, W.G., and Muller, W.E., 2003b, Cholesterol modulates amyloid beta-peptide’s membrane interactions. Pharmacopsychiatry, 36Suppl 2: S136–S143.PubMedGoogle Scholar
  17. Eckert, G.P., Wood, W.G., and Müller, W.E., 2001, Effects of aging and beta-amyloid on the properties of brain synaptic and mitochondrial membranes. J. Neural Transm. 108: 1051–1064.PubMedCrossRefGoogle Scholar
  18. Fletcher, T.G., and Keire, D.A., 1997, The interaction of beta-amyloid protein fragment (12–28) with lipid environments. Protein Sci., 6: 666–675.PubMedCrossRefGoogle Scholar
  19. Garrido, J.L., Godoy, J.A., Alvarez, A., Bronfman, M., and Inestrosa, N.C., 2002, Protein kinase C inhibits amyloid beta peptide neurotoxicity by acting on members of the Wnt pathway. FASEB J., 16: 1982–1984.PubMedGoogle Scholar
  20. Gimpl, G., Burger, K., and Fahrenholz, F., 1997, Cholesterol as modulator of receptor function. Biochemistry 36: 10959–10974.PubMedCrossRefGoogle Scholar
  21. Haass, C., and De Strooper, B., 1999, The presenilins in Alzheimer’s disease-proteolysis holds the Key. Science, 286: 916–919.PubMedCrossRefGoogle Scholar
  22. Hartmann, H., Eckert, A., Crews, F.T., Müller, W.E., 1996, b-amyloid amplifies PLC activity and Ca2+ signalling in fully differentiated brain cells of adult mice. Amyloid 3: 234–241.Google Scholar
  23. Hartmann, H., Eckert, A., and Müller, W.E., 1993, Beta-Amyloid protein amplifies calcium signalling in central neurons from the adult mouse. Biochem. Biophys. Res. Commun. 194: 1216–1220.PubMedCrossRefGoogle Scholar
  24. Hartmann, H., Eckert, A., and Müller, W.E., 1994, Apolipoprotein E and cholesterol affect neuronal calcium signalling: The possible relationship to beta-amyloid neurotoxicity. Biochem. Biophys. Res. Commun. 200: 1185–1192.PubMedCrossRefGoogle Scholar
  25. Haughey, N.J., and Mattson, M.P., 2003, Alzheimer’s amyloid beta-peptide enhances ATP/gap junction-mediated calcium-wave propagation in astrocytes. Neuromolecular. Med. 3: 173–180.PubMedCrossRefGoogle Scholar
  26. Hayashi, H., Mizuno, T., Michikawa, M., Haass, C., and Yanagisawa, K., 2000, Amyloid precursor protein in unique cholesterol-rich microdomains different from caveolae-like domains. Biochim. Biophys. Acta 1483: 81–90.PubMedGoogle Scholar
  27. Hirakura, Y., Satoh, Y., Hirashima, N., Suzuki, T., Kagan, B.L., and Kirino, Y., 1998, Membrane perturbation by the neurotoxic Alzheimer amyloid fragment beta 25–35 requires aggregation and beta-sheet formation. Biochem. Mol. Biol. Int. 46: 787–794.PubMedGoogle Scholar
  28. Igbavboa, U., Avdulov, N.A., Schroeder, F., and Wood, W.G., 1996, Increasing Age Alters Transbilayer Fluidity and Cholesterol Asymetry in Synaptic Plasma Membrane of Mice. J. Neurochem. 66: 1717–1725.PubMedCrossRefGoogle Scholar
  29. Kaiser, R.D., and London, E., 1998, Location of diphenylhexatriene (DPH) and its derivatives within membranes: comparison of different fluorescence quenching analyses of membrane depth. Biochemistry 37: 8180–8190.PubMedCrossRefGoogle Scholar
  30. Kanfer, J.N., Sorrentino, G., and Sitar, D.S., 1999, Amyloid beta peptide membrane perturbation is the basis for its biological effects. Neurochem. Res. 24: 1621–1630.PubMedCrossRefGoogle Scholar
  31. Kawahara, M., and Kuroda, Y., 2000, Molecular mechanism of neurodegeneration induced by Alzheimer’s beta-amyloid protein: channel formation and disruption of calcium homeostasis. Brain Res. Bull. 53: 389–397.PubMedCrossRefGoogle Scholar
  32. Keller, J.N., Pang, Z., Geddes, J.W., Begley, J.G., Germeyer, A., Waeg, G., and Mattson, M.P., 1997, Impairment of glucose and glutamate transport and induction of mitochondrial oxidative stress and dysfunction in synaptosomes by amyloid beta-peptide: Role of the lipid peroxidation product 4-hydroxynonenal. J. Neurochem. 69: 273–284.PubMedCrossRefGoogle Scholar
  33. Kirsch, C., Eckert, G.P., and Müller, W.E., 2002, Cholesterol attenuates the membrane perturbing properties of b-amyloid peptides. Amyloid 9: 149–159.PubMedGoogle Scholar
  34. Kojro, E., Gimpl, G., Lammich, S., Marz, W., and Fahrenholz, F., 2001, Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha-secretase ADAM 10. Proc. Natl. Acad. Sci. USA 98: 5815–5820.PubMedCrossRefGoogle Scholar
  35. Kremer, J.J., Pallitto, M.M., Sklansky, D.J., and Murphy, R.M., 2000, Correlation of beta-amyloid aggregate size and hydrophobicity with decreased bilayer fluidity of model membranes. Biochemistry 39: 10309–10318.PubMedCrossRefGoogle Scholar
  36. Lakowicz, J.R., 1983, Fluorescence Polarisation. In: Lakowicz, JR., (Ed.), Principles of Fluorescence Spectroscopy. Plenum Press, New York, pp. 112–151.Google Scholar
  37. Mason, R.P., Estermyer, J.D., Kelly, J.F., and Mason, P.E., 1996, Alzheimer’s disease amyloid beta peptide 25–35 is localized in the membrane hydrocarbon core: x-ray diffraction analysis. Biochem. Biophys. Res. Commun. 222: 78–82.PubMedCrossRefGoogle Scholar
  38. Mason, R.P., Jacob, R.F., Walter, M.F., Mason, P.E., Avdulov, N.A., Chochina, S.V., Igbavboa, U., and Wood, W.G., 1999, Distribution and Fluidizing Action of Soluble and Aggregated Amyloid Beta-Peptide in Rat Synaptic Plasma Membranes. J. Biol. Chem. 274: 18801–18807.PubMedCrossRefGoogle Scholar
  39. Matsuzaki, K., and Horikiri, C., 1999, Interactions of amyloid beta-peptide (1-40) with ganglioside-containing membranes. Biochemistry 38: 4137–4142.PubMedCrossRefGoogle Scholar
  40. Mattson, M.P., and Sherman, M., 2003, Perturbed signal transduction in neurodegenerative disorders involving aberrant protein aggregation. Neuromolecular. Med. 4: 109–132.PubMedCrossRefGoogle Scholar
  41. Mattson, M.P., Tomaselli, K.J., and Rydel, R.E., 1993, Calcium-destabilizing and neurodegenerative effects of aggregated beta-amyloid peptide are attenuated by basic FGF. Brain Res. 621:35–49.PubMedCrossRefGoogle Scholar
  42. McDonald, D.R., Brunden, K.R., and Landreth, G.E., 1997, Amyloid fibrils activate tyrosine kinase-dependent signaling and superoxide production in mtcroglia. J. Neurosci. 17: 2284–2294.PubMedGoogle Scholar
  43. McLaurin, J., and Chakrabartty, A., 1996, Membrane disruption by Alzheimer beta-amyloid peptides mediated through specific finding to either phospholipids or gangliosides-Implications for neurotoxicity. J. Biol. Chem. 271: 26482–26489.PubMedCrossRefGoogle Scholar
  44. McLaurin, J., and Chakrabartty, A., 1997, Characterization of the interactions of Alzheimer beta-amyloid peptides with phospholipid membranes. Eur. J. Biochem. 245: 355–363.PubMedCrossRefGoogle Scholar
  45. Mulders, F., van Langen, H., Van Ginkel, G., and Levine, Y.K., 1986, The static and dynamic behaviour of fluorescent probe molecules in lipid bilayers. Biochim. Biophys. Acta 859: 209–218.CrossRefGoogle Scholar
  46. Müller, W.E., Eckert, G.P., Scheuer, K., Cairns, N.J., Maras. A., and Gattaz, W.F., 1998, Effects of b-amyloid peptides on the fluidity of membranes from frontal and parietal lobes of human brain. High potencies of A beta 1-42 and A beta 1-43. Amyloid 5: 10–15.PubMedGoogle Scholar
  47. Müller, W.E., Kirsch, C., and Eckert, G.P., 2001, Membrane-disordering effects of beta-amyloid peptides. Biochem. Soc. Trans. 29: 617–623.PubMedCrossRefGoogle Scholar
  48. Müller, W.E., Koch, S., Eckert, A., Hartmann, H., and Scheuer, K., 1995, β-Amyloid peptide decreases membrane fluidity. Brain Res. 674: 133–136.PubMedCrossRefGoogle Scholar
  49. Olariu, A., Yamada, K., Mamiya, T., Hefco, V., and Nabeshima, T., 2002, Memory impairment induced by chronic intracerebroventricular infusion of beta-amyloid (1-40) involves downregulation of protein kinase C. Brain Res. 957: 278–286.PubMedCrossRefGoogle Scholar
  50. Oshima, N., Morishima-Kawashima, M., Yamaguchi, H., Yoshimura, M., Sugihara, S., Khan, K., Games, D., Schenk, D., and Ihara, Y., 2001, Accumulation of Amyloid beta-Protein in the Low-Density Membrane Domain Accurately Reflects the Extent of beta-Amyloid Deposition in the Brain. Am. J. Pathol. 158: 2209–2218.PubMedGoogle Scholar
  51. Palacino, J.J., Murphy, M.P., Murayama, O., Iwasaki, K., Fujiwara, M., Takashima, A., Golde, T.E., and Wolozin, B., 2001, Presenilin 1 regulates beta-catenin-mediated transcription in a glycogen synthase kinase-3-independent fashion. J. Biol. Chem. 276: 38563–38569.PubMedCrossRefGoogle Scholar
  52. Pike, C.J., Walencewicz, A.J., Kosmoski, J., Cribbs, D.H., Glabe, C.G., and Cotman, C.W., 1995, Structure-activity analyses of beta-amyloid peptides: contributions of the beta 25–35 region to aggregation and neurotoxicity. J. Neurochem. 64: 253–265.PubMedCrossRefGoogle Scholar
  53. Pike, C.J., Walencewicz A.J., Glabe, C.G., and Cotman, C.W., 1991, Aggregation-related toxicity of synthetic beta-amyloid protein in hippocampal cultures. Eur. J. Pharmacol. 207: 367–368.PubMedCrossRefGoogle Scholar
  54. Pirttilä, T., Soininen, H., Mehta, P.D., Heinonen, O., Lehtimaeki, T., Bogdanovic, N., Paljaervi, L., Kim, K.S., Kosunen, O., Winblad, B., Riekkinen, P.S., and Wisniewski, H.M., 1996, Apolipoprotein E genotype and amyloid load in Alzheimer disease and control brains. Neurobiol. Aging 18: 121–127.CrossRefGoogle Scholar
  55. Scheuer, K., Maras, A., Gattaz, W.F., Cairns, N., Förstl, H., and Müller, W.E., 1996, Cortical NMDA Receptor Properties and Membrane Fluidity are Altered in Alzheimer’s Disease. Dementia 7: 210–214.PubMedGoogle Scholar
  56. Shimohama, S., and Matsushima, H., 1995, Signal transduction mechanisms in Alzheimer disease. Alzheimer. Dis. Assoc. Disord. 9Suppl 2: 15–22.PubMedCrossRefGoogle Scholar
  57. Simons, K., and Ikonen, E., 2000, How cells handle cholesterol. Science 290: 1721–1726.PubMedCrossRefGoogle Scholar
  58. Simons, K., and Toomre, D., 2000 Lipid Rafts and Signal Transduction. Nature Rev. Mol. Cell Biol. 1: 31–39.CrossRefGoogle Scholar
  59. Sinha, S., and Lieberburg, I., 1999, Cellular mechanisms of beta-amyloid production and secretion. Proc. Natl. Acad. Sci. USA 96: 11049–11053.PubMedCrossRefGoogle Scholar
  60. Small, D.H., and McLean, C.A., 1999, Alzheimer’s disease and the amyloid beta protein: What is the role of amyloid? J. Neurochem. 73: 443–449.PubMedCrossRefGoogle Scholar
  61. Soomets, U., Mahlapuu, R., Tehranian, R., Jarvet, J., Karelson E., Zilmer, M., Iverfeldt, K., Zorko, M., Graslund, A., and Langel, U., 1999, Regulation of GTPase and adenylate cyclase activity by amyloid beta-peptide and its fragments in rat brain tissue. Brain Res. 850: 179–188.PubMedCrossRefGoogle Scholar
  62. Soto, C., Branes, M.C., Alvarez, J., and Inestrosa, N.C., 1994, Structural determinants of the Alzheimer’s amyloid beta-peptide. J. Neurochem. 63: 1191–1198.PubMedCrossRefGoogle Scholar
  63. Soto, C., Saborio, G.P., and Permanne, B., 2000, Inhibiting the conversion of soluble amyloid-beta peptide into abnormally folded amyloidogenic intermediates: relevance for Alzheimer’s disease therapy. Acta Neurol. Scand. Suppl, 176: 90–95.CrossRefGoogle Scholar
  64. Terzi, E., Holzemann, G., and Seelig, J., 1997, Interaction of Alzheimer beta-amyloid peptide( 1-40) with lipid membranes. Biochemistry 36: 14845–14852.PubMedCrossRefGoogle Scholar
  65. Torp, R., Head, E., Milgram, N.W., Hahn, F., Ottersen, O.P., and Cotman,. W., 2000, Ultrastructural evidence of fibrillar beta-amyloid associated with neuronal membranes in behaviorally characterized aged dog brains. Neuroscience 96: 495–506.PubMedCrossRefGoogle Scholar
  66. Waschuk, S., Elton, E.A., Darabie, A.A., Fraser, P.E., and McLaurin, J., 2001, Cellular membrane composition defines Ab-lipid interactions. J. Biol. Chem. 275: 33561–33568.CrossRefGoogle Scholar
  67. Wood, W.G., Eckert, G.P., Igbavboa, U., and Müller, W.E., 2003, Amyloid beta-protein interactions with membranes and cholesterol: causes or casualties of Alzheimer’s disease. Biochim Biophys Acta 1610: 281–290.CrossRefGoogle Scholar
  68. Wood, W.G., Schroeder, F., Avdulov, N.A., Chochina, S.V., and Igbavboa, U., 1999, Recent advances in brain cholesterol dynamics: transport, domains, and Alzheimer’s disease. Lipids 34: 225–234.PubMedCrossRefGoogle Scholar
  69. Wood, W.G., Schroeder, F., Igbavboa, U., Avdulov, N.A., Chochina, S.V., 2002, Brain membrane cholesterol domains, aging and amyloid beta-peptides. Neurobiol. Aging 23: 685.PubMedCrossRefGoogle Scholar
  70. Yamaguchi, H., Maat-Schieman, M.L., van Duinen, S.G., Prins, F.A., Neeskens, P., Natte, R., and Roos, R.A., 2000, Amyloid beta protein (Abeta) starts to deposit as plasma membrane-bound form in diffuse plaques of brains from hereditary cerebral hemorrhage with amyloidosis-Dutch type, Alzheimer disease and nondemented aged subjects. J. Neuropathol. Exp. Neurol. 59: 723–732.PubMedGoogle Scholar
  71. Yankner, B.A., Duffy, L.K., Kirschner, D.A., 1990, Neurotrophic and neurotoxic effects of amyloid-beta protein: Reversal by tachykinin neuropeptides. Science 250: 279–282.PubMedCrossRefGoogle Scholar
  72. Ye, C.P., Selkoe, D.J., and Hartley, D.M., 2003, Protofibrils of amyloid beta-protein inhibit specific K+ currents in neocorrical cultures. Neurobiol. Dis. 13: 177–190.PubMedCrossRefGoogle Scholar
  73. Yeagle, P.L., 1989, Lipid regulation of cell membrane structure and function. FASEB J. 3: 1833–1842.PubMedGoogle Scholar
  74. Yip, CM., Elton, E.A., Darabie, A.A., Morrison, M.R., and McLaurin, J., 2001, Cholesterol, a modulator of membrane-associated Abeta-fibrillogenesis and neurotoxicity. J. Mol. Biol. 311: 723–734.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Gunter P. Eckert
    • 1
  • W. G. Wood
    • 2
  • W. E. Müller
    • 1
  1. 1.Department of PharmacologyZAFES, Biocenter University of FrankfurtGermany
  2. 2.Department of PharmacologyUniversity of Minnesota School of MedicineMinneapolisUSA

Personalised recommendations